Acetazolamide to Improve Clinically Important Outcomes in Obstructive Sleep Apnea Patients with a High Loop Gain Endotype

乙酰唑胺可改善具有高环增益内型的阻塞性睡眠呼吸暂停患者的临床重要结果

• 批准号: 10524708
• 负责人: Christopher Nikolaus Schmickl
• 金额: $ 17.26万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10524708
• 关键词: Acetazolamide; Address; Adult; Affect; Apnea; Arousal; Award; Biometry; Blood Pressure; Body mass index; Carbonic Anhydrase Inhibitors; Clinic; Clinical; Clinical Trials; Cognition; Continuous Positive Airway Pressure; Cross-Over Trials; Data; Development; Development Plans; Diuretics; Doctor of Philosophy; Dose; Drowsiness; Enrollment; Epidemiology; Equilibrium; Functional disorder; Goals; Health; Hypertension; Hypoxemia; Hypoxia; Impaired cognition; Impairment; Individual; Intervention; Long-Term Effects; Longitudinal Studies; Measures; Medicine; Mentored Patient-Oriented Research Career Development Award; Mentors; Mission; Myocardial Infarction; National Heart, Lung, and Blood Institute; Neurocognitive; Obstructive Sleep Apnea; Outcome; Oxygen; Pathogenesis; Patient Care; Patient Outcomes Assessments; Patients; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Physicians; Physiological; Physiology; Placebo Control; Placebos; Positioning Attribute; Publishing; Quality of life; Questionnaires; Randomized; Research; Research Infrastructure; Research Personnel; Risk; Scientist; Severities; Sleep; Sleep Apnea Syndromes; Sleep Fragmentations; Sleep disturbances; Stimulant; Stroke; Subgroup; Testing; Time; Training; Translating; United States National Institutes of Health; Vision; Work; alternative treatment; awake; base; blood pressure reduction; career development; cost; design; drug development; experience; functional outcomes; hands on research; hangover; improved; indexing; individual patient; insight; instrument; novel; personalized care; personalized intervention; response; responsible research conduct; sedative; skills; sleep quality; standard of care; vehicular accident; vigilance

PROJECT SUMMARY/ABSTRACT Research Plan: Worldwide, one in 8 adults has obstructive sleep apnea (OSA) which results in disturbed sleep, daytime sleepiness, and increases the risk for many health issues including cognitive impairment, heart attacks and strokes. Unfortunately, half of OSA patients are unable to use continuous positive airway pressure therapy, and due to limited alternative options, most remain untreated. But OSA is a heterogenous condition, and mechanisms underlying OSA in individual patients (“endotypes”) can now be quantified, allowing targeted manipulation and providing a clear avenue to develop OSA drug therapy as an alternative for such patients. Ventilatory instability (“high loop gain”) contributes to OSA pathogenesis in one third of patients. The PI’s data suggests that acetazolamide—a safe, low-cost ($0.66/day), once daily drug which lowers loop gain—can markedly improve OSA and its sequelae in some patients, and may be particularly beneficial for patients with a high loop gain endotype. However, prior studies generally did not measure loop gain and data on clinically important outcomes are scarce. To define better acetazolamide’s value for patient-care, the PI will conduct a randomized, placebo-controlled, crossover trial, testing if 4 weeks of acetazolamide in general OSA patients improves OSA severity (aim 1) and clinically important outcomes (aim 2), and assess predictors/mechanisms (including loop gain) of changes in these outcomes (aim 3) to help identify likely responders more precisely. Career Development Plan: The PI, Dr Chris Schmickl MD/PhD, has a strong background in epidemiology, biostatistics and clinical sleep medicine. This K23 award will provide him with the protected time and training to achieve his long-term goal of becoming an independent physician-scientist, translating physiological insights into precision pharmacotherapy for patients with OSA who are unable to use current therapies. To achieve this long-term goal Dr Schmickl will develop advanced skills in three key domains which perfectly align with the expertise of his diverse and outstanding mentor/advisor team from UC San Diego: 1) OSA patho- physiology (Drs Malhotra/Owens/Nemati); 2) Designing/executing clinical trials (Dr Jain); and 3) Assessing clinically important outcomes (Drs Banks/Taub). Based on a gap analysis, a comprehensive training plan was designed which carefully balances hands-on research experiences with complementary coursework, and emphasizes the importance of a responsible conduct of research. Clear objectives and milestones have been defined to track progress during the award. The acquired data and skills will allow the PI to expand on this work with an R01 studying the long-term effects of acetazolamide (and/or other interventions) in patho- physiologically defined subgroups of likely responders. More broadly, this award will enable him to develop novel, high-impact, precision interventions for the many currently untreated OSA patients, thereby joining the NHLBI mission to enhance the health of all individuals so that they can live longer and more fulfilling lives.

项目概要/摘要 研究计划：在全球范围内，八分之一的成年人患有阻塞性睡眠呼吸暂停 (OSA)，这会导致精神不安 睡眠、白天嗜睡，并增加许多健康问题的风险，包括认知障碍、心脏 不幸的是，一半的 OSA 患者无法使用持续气道正压通气。 治疗，并且由于替代选择有限，大多数仍未得到治疗，但 OSA 是一种异质性疾病， 现在可以量化个体患者 OSA 的潜在机制（“内型”），从而实现有针对性的治疗 操纵并为开发 OSA 药物治疗作为此类患者的替代方案提供了明确的途径。 PI 的数据显示，三分之一的患者发生 OSA 的原因是通气不稳定（“高循环增益”）。 表明乙酰唑胺——一种安全、低成本（0.66 美元/天）、每日一次的药物，可降低环路增益——可以 显着改善某些患者的 OSA 及其后遗症，对于患有以下疾病的患者可能特别有益 高环路增益内型。然而，先前的研究通常没有测量环路增益和临床数据。 为了更好地定义乙酰唑胺对患者护理的价值，PI 将进行一项研究。 随机、安慰剂对照、交叉试验，测试是否对一般 OSA 患者服用 4 周乙酰唑胺 改善 OSA 严重程度（目标 1）和临床重要结果（目标 2），并评估预测因素/机制 （包括环路增益）这些结果的变化（目标 3），以帮助更准确地识别可能的响应者。 职业发展计划：首席研究员 Chris Schmickl 博士（医学博士/博士）拥有深厚的流行病学背景， 该 K23 奖项将为他提供生物统计学和临床​​睡眠医学的受保护时间和培训。 实现成为一名独立医师科学家的长期目标，转化生理学见解 为无法使用现有疗法的 OSA 患者进行精准药物治疗。 为了实现这一长期目标，施米克尔博士将在三个关键领域培养高级技能，这将完美地实现这一目标。 与他来自加州大学圣地亚哥分校的多元化且杰出的导师/顾问团队的专业知识相一致：1) OSA 病理- 生理学（Malhotra 博士/Owens/Nemati 博士）；2) 设计/执行临床试验（Jain 博士）；以及 3) 评估 临床上重要的结果（Drs Banks/Taub）基于差距分析，制定了全面的培训计划。 精心设计，平衡实践研究经验与补充课程作业，以及 强调了负责任的研究行为的重要性。 定义为跟踪奖励期间的进展情况，PI 可以在此基础上进行扩展。 与 R01 合作研究乙酰唑胺（和/或其他干预措施）对病理的长期影响 更广泛地说，这个奖项将使他能够发展生理上定义的可能反应者亚组。 为许多目前未经治疗的 OSA 患者提供新颖、高效、精准的干预措施，从而加入 NHLBI 的使命是增强所有人的健康，使他们能够活得更长久、更充实的生活。